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Published ahead of print on March 16, 2006, doi:10.1164/rccm.200508-1218OC

Am. J. Respir. Crit. Care Med., Volume 173, Number 11, June 2006, 1208-1215

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Submitted on August 7, 2005
Accepted on March 16, 2006

Regional Fibroblast Heterogeneity in the Lung: Implications for Remodeling

Chakradhar Kotaru1*, Kathryn J Schoonover2, John B Trudeau2, Mai-Lan Huynh1, XiuXia Zhou2, Haizhen Hu2, and Sally E Wenzel1

1 Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado, USA; Department of Medicine, University of Colorado Health Sciences Center, Denver, Colorado, USA, 2 Department of Medicine, National Jewish Medical and Research Center, Denver, Colorado, USA

* To whom correspondence should be addressed. E-mail: kotaruc{at}njc.org.

Rationale: Excessive deposition of extracellular matrix occurs in proximal airways of asthmatics, but fibrosis in distal lung has not been observed. Whether differing fibrotic capacities of fibroblasts from these two regions contribute to this variability is unknown. Objectives: We compared morphologic and functional characteristics of fibroblasts isolated from proximal airways and distal lung parenchyma to determine phenotypic differences. Methods: Concurrent proximal airway and distal lung biopsies were obtained from asthmatics using bronchoscopy to isolate airway and distal lung fibroblasts respectively. The following characteristics were compared: morphology, proliferation, {alpha}-smooth muscle actin expression, and synthesis of pro-collagen-1 and eotaxin-1. Results: Airway fibroblasts (AF) are morphologically distinct from distal lung fibroblasts (DLF); they are larger (2.3 fold greater surface area vs. matched DLF, p=0.02), stellate in appearance with more cytoplasmic projections compared to the spindle-shaped DLF. AF synthesized more procollagen-1 than DLF at baseline (2-fold higher, p=0.003) and after TGF-{beta} stimulation (1.4-fold higher, p=0.02). Similarly, AF produced more eotaxin-1 than DLF at baseline (2.5-fold higher, p=0.004) and after IL-13 stimulation (13-fold higher, p=0.0001). In contrast, DLF proliferate more than AF with serum stimulation (about 6-fold greater, p=0.03). Unstimulated DLF also expressed more {alpha}-smooth muscle actin than corresponding AF (p=0.006). Conclusions: These studies suggest that at least two phenotypes of fibroblasts exist in the lung. These phenotypic differences may partially explain the variable responses to injury and repair between proximal airways and distal lung/parenchyma in asthma and other respiratory diseases.
Key words: Fibroblast, Remodeling, Asthma, TGF-beta, Interleukin-13




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